The Johns Hopkins proposal for a Specialized Center of Research in Sudden Cardiac Death (SCD) seeks to improve our understanding of SCD by bringing state-of-the-art molecular approaches to bear on the problem. We start with the premise that, if we can learn in detail how cardiac excitability works at the cellular and molecular levels, this knowledge can then be profitably applied to the prevention of SCD and to the rational identification and treatment of patients at risk for SCD. Although our proposal impacts broadly upon SCD, the specific clinical problem which we seek to elucidate is the pathogenesis of SCD in patients with heart failure. Our proposal consists of five projects and one core, including investigators from two clinical and two basic science departments. Project 1, directed by Dr. Eduardo Marban, probes the function of sodium and calcium at the molecular level. Project 2, directed by Dr. David Yue, seeks to determine how and where antiarrhythmic agents block the pores of sodium channels. Dr. William Agnew investigates the molecular properties of IP3 receptors, which regulate calcium release from intracellular stores. In addition to probing the basic mechanisms of excitation, the SCOR will explore the feasibility and advisability of genetic approaches to the diagnosis and treatment of patients prone to SCD. The final two projects test the hypothesis that specific alterations in potassium channel gene expression in heart failure predispose to SCD by producing abnormalities of repolarization. The project directed by Drs. Arthur Feldman and David Kass, investigates the changes in ion channel gene expression in an animal model of heart failure and SCD. The clinical evaluation of such changes is the subject of Project 8, in which Dr. Gordon Tomaselli and coworkers develop and test new approaches for quantifying abnormalities of repolarization and of ion channel gene expression in patients with heart failure.